Uptake, decreased, mechanism

Acetylcholine synthesis and neurotransmission requires normal functioning of two active transport mechanisms. Choline acetyltransferase (ChAT) is the enzyme responsible for ACh synthesis from the precursor molecules acetyl coenzyme A and choline. ChAT is the neurochemical phenotype used to define cholinergic neurons although ChAT is present in cell bodies, it is concentrated in cholinergic terminals. The ability of ChAT to produce ACh is critically dependent on an adequate level of choline. Cholinergic neurons possess a high-affinity choline uptake mechanism referred to as the choline transporter (ChT in Fig. 5.1). The choline transporter can be blocked by the molecule hemicholinium-3. Blockade of the choline transporter by hemicholinium-3 decreases ACh release,... 

Fig. 18. (a) Representation of the tumor hypoxic state (diagram adapted from Ref. (83a). Arrow direction indicates decrease in pC>2 (< 1 mmHg), achieved for tumor depths larger than 100 pm (b) proposed mechanism for redox-mediated retention of [Cu(ATSM)] in hypoxic cells (101-105). Note Contrary to common belief cell membrane crossing solely by direct diffusion is unlikely for compounds of this family is unlikely, as indicated by fluorescence imaging work on aromatic Zn(II) analogs (vide infra). Endocytosis is the more likely uptake mechanism (112-113). 

A person who responds to an unusually low dose of a drug is called h y per reactive. Supersensitivity refers to increased responses to low doses only after denervation of an organ. At least three mechanisms are responsible for supersensitivity (1) increased receptors, (2) reduction in tonic neuronal activity, and (3) decreased neurotransmitter uptake mechanisms. 

The mechanism by which the more recently used WR-2721 (Fig. 8) reduces nephrotoxicity is not very well understood. WR-2721 protects against nephrotoxicity when administered just prior to cis-Pt (144,145) and it is known that WR-2721 is preferentially taken up by normal cells and not by tumor cells (146). Recently, it was concluded that the uncharged form of the dephosphorylated WR-2721 (known as WE-1065) is the actual species taken up by both normal and tumor cells (147). It has been proposed that the conversion of WR-2721 to WR-1065 is slower in tumors, compared with normal tissues (147), possibly because tumors generally have lower levels of alkaline phosphatase (148). Furthermore, it has been proposed (147) that once formed, WR-1065 will have a decreased uptake rate in tumors, probably as a consequence of their lower pH (149) as compared with normal tissues i.e., the neutral form of WR-1065 will only constitute 0.1% of the total drug present at pH 7 and 1% of the total at pH 8. The reactive WR-1065 is likely to bind directly to cis-Pt, thereby preventing side reactions of cis-Pt. 

The first entirely synthetic derivative, fluvastatin (see Ref. [19]), and its subsequent derivative, atorvastatin, have a lipid solubility that is intermediate between pravastatin and the lactone prodrugs (see Tab. 4.2), and consequently their liver specificities are less expressed. In order to benefit from selective statin uptake mechanism into the liver cells and thereby decrease passive diffusion into other cell types, the recently introduced rosuvastatin molecule was purposefully made more hydrophilic by the introduction of a sulfonamide group. Indeed, the ratio of IC5 values measured in fibroblasts and hepatocyte cultures became considerable higher than that of atorvastatin (see Tab. 4.1). The pronounced differences of inhibitory potency, lipophilicity and the extent of active OATP-linked transport jointly... 

Impaired uptake Fusidic acid Penicillins QACs 4-Quinolones Tetracyclines Plasmid-borne mechanism for decreased uptake Mutational alterations to porins Plasmid-encoded porin modifications Mutational alterations to porins Failure to accumulate (efflux more important)... 

Decreased uptake as a mechanism of resistance was also observed in houseflies resistant to organochlorine, organophosphate, and carbamate insecticides. Resistant strains had higher total lipids, monoglycerides, diglycerides, fatty acids, sterols, and phospholipids in the cuticle than did the susceptible strain (Patil and Guthrie, 1979). 

The quantitative relationship between cholesterol intake and cholesterol levels is still controversial, especially because in humans, there appears to be a high individual variability in processing of dietary cholesterol. However, numerous animal and human studies support the concept that dietary cholesterol can raise LDL-cholesterol levels and change the size and composition of these particles as well. LDL particles become larger in size and enriched in cholesterol esters. Mechanisms contributing to these events include an increase in hepatic synthesis of apoB-containing lipoproteins, increased conversion of VLDL remnants to LDL, or a decrease in the fractional catabolic rate for LDL. Reduced LDL receptor activity due to an increase in hepatic cholesterol content, secondary to excess dietary cholesterol, may lead to a decreased uptake of both LDL and VLDL remnants. 

Fluoroquinolones must penetrate bacteria to reach their target, DNA gyrase. The second mechanism of fluoroquinolone resistance is decreased cell wall permeability. The fluoroquinolones diffuse through porin channels in the outer membrane of Gram-negative bacteria. Mutation results in a decrease in porin channel proteins, resulting in decreased uptake of the fluoroquinolones into bacterial cells. Alterations in a wide range of outer membrane proteins in Pseudomonas spp. result in resistance. From these mutations, the increase in MIC of the fluoroquinolones is relatively low (2-to 32-fold). Flowever, there is cross-resistance with unrelated antibiotics, most frequently cefoxitin, chloramphenicol, trimethoprim and tetracycline. 

It is important to note that depleted striatal DA storage inDAT-KO mice cannot be explained by a deficit in VMAT2-mediated vesicular uptake mechanisms. Neither VMAT2 mRNA in the SN or tetrabenazine binding, VMAT2 protein levels, nor functional vesicular uptake of DA in the striatum was significantly altered in these mice (39). Thus, the depletion of the DA storage pools and the decreased... 

The concentration of ascorbate in the human plasma is 25 pM and above. Cells take up ascorbate by a Na -coupled uptake mechanism against a concentration gradient. A marked stereo-selectivity for L-ascorbic acid relative to D-isoascorbic acid in their cellular transport has been shown by Franceschi et al. [12]. The same transport is also important in the intestine. The nutritional supply of ascorbic acid is the only source for this vitamin in humans, primates, and guinea pigs. Other mammals are able to produce ascorbic acid. There exists sufficient evidence for an active role of ascorbate as an antioxidant in vivo. Decreased ascorbic acid will increase lipid peroxidation and decrease vitamin E and is connected with oxidative DNA damage. The supply of ascorbate in some cases will reduce the amount of oxidative damage in diseases that... 

Resistance to pesticides arises primarily through changes in the sensitivity of the site of action or in the metabolism of the pesticide (25,27.28). Many pesticides are activated metabolically. While it is theoretically possible to generate resistance through reduced activation, it seems much more common to observe increased detoxification in resistant strains. In some cases decreased uptake or enhanced excretion also contribute. It is an obvious prerequisite for any type of scientifically-based attempt to combat resistance that the resistance mechanism and its genetic basis must be defined. 

Mechanisms of action and resistance Cytarabine (cytosine arabinoside) is a pyrimidine antimetabolite. The drug is activated by kinases to AraCTP, an inhibitor of DNA polymerases. Of all the antimetabolites, cytarabine is the most specific for the S phase of the tumor cell cycle. Resistance to cytarabine can occur as a result of its decreased uptake or its decreased conversion to AraCTP. 

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